Liver disease (LD) has risen as a major cause of morbidity and mortality in antiretroviral therapy (ART)-treated HIV-1-infected individuals. A growing body of evidence suggests that HIV-1 alters and accelerates the pathologic processes driving LD via systemic inflammation; however, the role of neutrophils and innate immune dysregulation in these processes has not been evaluated. This application proposes that innate immune dysregulation mediated by changes in macrophage and neutrophil populations in gut- associated lymphoid tissue (GALT) and liver plays a fundamental role in HIV-1 disease progression. Neutrophils, the most abundant immune cell population in the body, are specifically geared for a sensitive detection of invading microbial and viral pathogens. GALT epithelial damage in both HIV-1 and SIV infections is temporally and spatially associated with a significant accumulation of neutrophils that directly contribute to mucosal damage. IL-17 serves as a master regulator of neutrophil function and, in conjunction with IL-10, it is required for an induction of anti-inflammatory macrophages that clear apoptotic neutrophilic infiltrates via efferocytosis and promote healing and resolution of local and systemic inflammation. The first underlying hypothesis of this proposal is that the depletion of IL-17-producing cells in the GALT of HIV-1-infected individuals blocks the induction of anti-inflammatory efferocytic tissue macrophages and causes polarization towards pro-inflammatory phenotype. This results in an accumulation of activated neutrophils that undergo NETosis and drive tissue damage in intestinal mucosa. Factors released as a result of ongoing GALT inflammation induce systemic recruitment of a population of activated neutrophils with specific phenotype, expression profile, and high capacity for NETosis. The second principal hypothesis is that HIV-1 infection is associated with a significantly decreased frequency of Kupffer cells (KCs) exhibiting anti-inflammatory phenotype and a significant shift towards blood monocyte-derived proinflammatory KCs. This state is not reversed following ART, possibly due to the depletion of self-renewing tissue-resident KC progenitors. Activated neutrophils interact with Kupffer cells and platelet and undergo NETosis in liver microvasculature. In the course of HIV-1 infection, this mechanism causes chronic liver inflammation, portal hypertension, activation of hepatic stellate cells, and results in a progression to non-alcoholic steatohepatitis (NASH) and liver fibrosis. Thus, we propose that two simultaneous hits to innate immune populations in primary and secondary mucosal firewalls, the GALT and the liver, drive disease progression in HIV-1/AIDS. We propose to determine the effect of neutrophil activation and innate immune dysregulation in GALT and liver on the progression of LD in ART- treated HIV-1-infected individuals. Importantly, since functional dysregulation of neutrophil population and neutrophil-macrophage interaction can be pharmacologically targeted, understanding of the underlying pathogenic mechanisms will lead to novel treatment approaches in HIV-1 infection and other chronic inflammatory conditions.